US7883697B1 - Fermented milk or vegetable proteins comprising receptor ligand and uses thereof - Google Patents

Fermented milk or vegetable proteins comprising receptor ligand and uses thereof Download PDF

Info

Publication number
US7883697B1
US7883697B1 US11/660,659 US66065905A US7883697B1 US 7883697 B1 US7883697 B1 US 7883697B1 US 66065905 A US66065905 A US 66065905A US 7883697 B1 US7883697 B1 US 7883697B1
Authority
US
United States
Prior art keywords
receptor
alpha
receptors
heart rate
fermented
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related, expires
Application number
US11/660,659
Other languages
English (en)
Inventor
Bénédicte Flambard
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Chr Hansen AS
Original Assignee
Chr Hansen AS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Chr Hansen AS filed Critical Chr Hansen AS
Assigned to CHR-HANSEN A/S reassignment CHR-HANSEN A/S ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: FLAMBARD, BENEDICTE
Application granted granted Critical
Publication of US7883697B1 publication Critical patent/US7883697B1/en
Expired - Fee Related legal-status Critical Current
Adjusted expiration legal-status Critical

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23C—DAIRY PRODUCTS, e.g. MILK, BUTTER OR CHEESE; MILK OR CHEESE SUBSTITUTES; MAKING THEREOF
    • A23C9/00—Milk preparations; Milk powder or milk powder preparations
    • A23C9/12—Fermented milk preparations; Treatment using microorganisms or enzymes
    • A23C9/123—Fermented milk preparations; Treatment using microorganisms or enzymes using only microorganisms of the genus lactobacteriaceae; Yoghurt
    • A23C9/1234—Fermented milk preparations; Treatment using microorganisms or enzymes using only microorganisms of the genus lactobacteriaceae; Yoghurt characterised by using a Lactobacillus sp. other than Lactobacillus Bulgaricus, including Bificlobacterium sp.
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/20—Milk; Whey; Colostrum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
    • C12N1/20—Bacteria; Culture media therefor
    • C12N1/205—Bacterial isolates
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P1/00—Preparation of compounds or compositions, not provided for in groups C12P3/00 - C12P39/00, by using microorganisms or enzymes
    • C12P1/04—Preparation of compounds or compositions, not provided for in groups C12P3/00 - C12P39/00, by using microorganisms or enzymes by using bacteria
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12R—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES C12C - C12Q, RELATING TO MICROORGANISMS
    • C12R2001/00—Microorganisms ; Processes using microorganisms
    • C12R2001/01—Bacteria or Actinomycetales ; using bacteria or Actinomycetales
    • C12R2001/225—Lactobacillus

Definitions

  • the present invention relates to compositions comprising receptor ligands obtainable by a process comprising fermenting a food material, comprising animal milk or vegetable proteins, with at least one lactic acid bacterium to obtain a fermented food material which comprises active components capable of affecting specific adrenoreceptors and/or serotonin receptors and which is useful e.g. for reducing and/or stabilizing heart rate, for treatment and/or relief of erectile dysfunctions and/or for treatment and/or relief of benign prostate hypertrophy (BPH), in a mammal.
  • BPH benign prostate hypertrophy
  • CAD coronary artery disease
  • CHD coronary heart disease
  • CAD and CHD is a “hardening” of the arteries on the surface of the heart, where the term “hardening” refers to a condition that causes the arteries to become so narrowed and stiff that the free flow of blood is blocked.
  • Lower heart rate is related with better outcome and in particular with a reduced risk of arrhythmias. Higher heart rate may reflect a higher metabolic rate and lower vagal tone thus increasing ischemic risk. Furthermore higher heart rates may also deteriorate ventricular function (Lombardi, F in Zaza et al., 2001). Thus it is not surprising that it has been reported that an important risk factor associated with CAD or CHD is a high heart rate. CAD or CHD is frequently treated with medications. These medications fall into different categories such as:
  • Beta blockers that reduce the workload of the heart by blocking certain chemicals from binding to beta-receptors in the heart.
  • Calcium channel blockers that increase blood flow through the heart and may reduce the workload of the heart by blocking calcium ions from signalling the blood vessels to constrict or tighten.
  • Anti platelets e.g. aspirin
  • Anti platelets that inhibit the formation of blood clots by decreasing the ability of platelets (microscopic particles found in the blood) to bind together and form a blood clot.
  • the prevention of a high heart rate in the early stage of the development of the disease can be an alternative to treatment of high heart rate with drugs.
  • a large number of food derived bioactive compounds are currently considered as beneficial for the general well being or as health promoting.
  • the article of Yamamoto et al. discloses that milk fermented with a starter containing Lactobacillus helveticus and Saccharomyces cerevisiae reduces the systolic and diastolic blood pressure, yet no changes were observed in other indexes, including pulse rate.
  • WO0185984 (Davisco International Foods, Inc.) also relates to peptides having anti-hypertensive effect (blood reducing effect), where the peptides from an enzymatic digest of whey protein. Changes in heart rate and blood pressure were measured. A significant reduction in mean arterial blood pressure was observed, and except for the observation of the 75 mg/kg dose, which elicited a decrease in heart rate, no significant difference between the heart rate responses occurred at the doses of 30 and 150 mg/kg.
  • the problem to be solved by the present invention is to provide an alternative composition useful for reducing heart rate and/or for the relief and/or treatment of benign prostate hypertrophy (BPH) ad/or erectile dysfunction.
  • BPH benign prostate hypertrophy
  • the solution is based on that the present inventor surprisingly has identified that by fermenting a food material, preferably milk, with a lactic acid bacterium (LAB), result in that active components that are ligands of several specific adreno-receptors and also serotonin-receptors and which effect the above mentioned diseases and conditions, are obtained.
  • a food material preferably milk
  • LAB lactic acid bacterium
  • a first aspect of the invention relates to the use of a composition obtainable by a process comprising fermenting a food material, which comprises animal milk or vegetable proteins, with at least one lactic acid bacterium to obtain a fermented food material which comprises at least one component that is a ligand of an adrenergic or a serotonin receptor for the manufacture of a product for reducing the heart rate in a mammal.
  • BPH benign prostate hyperthrophy
  • the invention provides a fermented food material having heart rate reducing properties and/or which is useful for the prevention and/or treatment of benign prostate hyperthrophy (BPH) and/or erectile dysfunction in a mammal and comprising at least one component that is a ligand of an adrenergic or a serotonin receptor produced by the fermentation of the food material with at least one lactic acid bacterium strain.
  • BPH benign prostate hyperthrophy
  • a food material fermented with Lactobacillus helveticus strain CHCC5951 (DSM 14998) and/or Streptococcus thermophilus is a preferred embodiment.
  • Food comprising living bacteria is frequently claimed to be particular healthy to ingest (i.e. probiotics).
  • the invention provides a fermented food material comprising living bacteria having heart rate reducing properties and/or which is useful for the prevention and/or treatment of benign prostate hyperthrophy (BPH) and/or erectile dysfunction in a mammal is provided.
  • the fermented food product comprises living bacterial cells of Lactobacillus helveticus strain DSM 14998 and/or Streptococcus thermophilus or mutants thereof.
  • the invention describes the use of the fermented food material or the component that is a ligand of the alpha- or beta-family of adrenoreceptors and/or serotonin receptors isolated therefrom for the manufacture a medicament for the treatment or relief of a coronary artery disease (CAD) or a coronary heart disease (CHD) such as angina pectoris, hypertension, atherosclerosis, stroke, myocardial infarcation, cerebral infarction, and restenosis following angioplasty, arrhythmia, tachyarrythmia, congestive heart failure (CHF), aortic valve regurgitation, chronic renal failure, dyslipidemia, dyslipoproteinemia. and/or for the treatment and/or relief of benign prostate hypertrophy (BPH) and/or erectile dysfunctions.
  • CAD coronary artery disease
  • CHD coronary heart disease
  • angina pectoris such as angina pectoris, hypertension, atherosclerosis, stroke, myocardial infar
  • the term “for reducing the heart rate in a mammalian” denotes reduction of heart rate in relation to the heart rate before administration of the composition as described herein.
  • the heart rate reducing properties should be determined in an animal model.
  • the fermented product is administered to spontaneous hypertensive rats (SHR) by gavage and determine the heart rate for 24 hours after gavage by telemetry in conscious SHR at different time points.
  • Placebo should preferably be the corresponding unfermented food material such as e.g. unfermented milk.
  • a model based on normotensive Wistar rats as described in Example 4 can be used to assess the reduction of heart rate.
  • ligand of an receptor is used to describe a component that can bind to the receptor and thereby it may act stimulatory (an agonist) or inhibitory (an “antagonist”). Finally it may compete for the receptor.
  • Adrenoreceptors also known as “adrenergic receptor” are receptors for noradrenaline and adrenalin.
  • serotonin receptor(s) refer to the serotonin receptors that binds [ 3 H]5-hydroxytryptamine as described by Peroutka (1979).
  • lactic acid bacterium designates a group of Gram positive, catalase negative, non-motile, microaerophilic or anaerobic bacteria that ferment sugar with the production of acids including lactic acid as the predominantly produced acid, acetic acid, formic acid and propionic acid.
  • the lactic acid bacterium is a bacterium of the phylium Firmicutes, more preferably of the class Bacilli, even more preferably of the order Lactobacillales.
  • a preferred lactic acid bacterium is a bacterium of the family Lactobacillaceae, more preferably of the genus Lactobacillus .
  • it is a Lactobacillus helveticus strain.
  • lactic acid bacteria are found among Lactococcus spp., Streptococcus spp., Lactobacillus spp., Leuconostoc spp., Pediococcus spp., Brevibacterium spp. and Propionibacterium spp. Additionally, lactic acid producing bacteria belonging to the group of the strict anaerobic bacteria, bifidobacteria, i.e. Bifidobacterium spp. which are frequently used as food starter cultures alone or in combination with lactic acid bacteria, are generally included in the group of lactic acid bacteria.
  • Embodiment(s) of the present invention is described below, by way of example(s) only.
  • the food material should comprise animal milk proteins or vegetable proteins.
  • animal milk proteins preferably enumerated by, for example milk protein components, such as whole or defatted animal milk or milk casein.
  • milk protein components such as whole or defatted animal milk or milk casein.
  • milk is from cows ( Bos taurus ).
  • Food material with vegetable proteins may preferably be enumerated by, for example corn, corn protein, wheat, wheat protein, soybean, defatted soybean or soybean protein.
  • lactic acid bacteria as described herein provides directly after fermentation a useful amount of the active components that are ligands of specific adrenergic receptors or a serotonin receptor.
  • beta receptors comprising beta-1 and beta-2
  • alpha-1 receptors and the alpha-2 receptors.
  • alpha-1 receptors and the alpha-2 receptors.
  • G-protein coupled receptors linked variously to the adenylate cyclase and phosphoinosisitidase second messenger pathway.
  • norepinepherine noradrenaline
  • epinephrine epinephrine epinephrine
  • the alpha-adreneregic receptors are important mediators of sympathetic nervous system responses, particularly those involved in cardiovascular homeostasis, such as arteriolar smooth muscle constriction and cardiac contraction all of which may lead to increased blood pressure and heart rate.
  • the beta-adrenergic receptors plays important role in the regulation of the cardiovascular system.
  • the stimulation of the contractility of the heart e.g. is mediated via activation of the beta-1 adrenergic and beta-2 adrenergic receptors, and increased heart rate is induced via beta-1 adreneregic receptors. Consequently antagonists of these receptors can be useful to decrease or stabilize the heart rate.
  • serotonin receptor antagonists have been ascribed numerous actions in the central nervous system they also appear to be involved in the regulation of the cardiovascular system.
  • the clinically investigated serotonin receptor antagonist, ketaserin has been found to be an effective anti-hypertensive agent.
  • the anti-hypertensive effect may not be ascribed solely to the serotonin receptor antagonizing activity of ketaserin since ketaserin may also block alpha-1 adreno receptors (Borne, 1994).
  • one embodiment of the invention is the use of a composition which comprise antagonists against a receptor selected from the group of receptors comprising alpha-adrenergic receptors, beta-adrenergic receptors and serotonin receptors for the manufacture of a product for reducing the heart rate in a mammal.
  • fermentation of cow milk according to the invention produces compounds that are ligands (most likely antagonists) of number of alpha- and beta-adrenoceptors, including the alpha 1 A-, the alpha 1 B-, the alpha 2A (h)-, the alpha 2B (h)-, the alpha 2C (h)-, the beta 1 (h)-, the beta 2 (h)- and the beta 3 (h)-adrenergic receptor and even serotonin receptors.
  • an embodiment of the present invention is the use of a composition which comprise antagonists against a receptor selected from the group of receptors comprising the alpha 1 A-, the alpha 1 B-, the alpha 2A (h)-, the alpha 2B (h)-, the alpha 2C (h)-, the beta 1 (h)-, the beta 2 (h)- and the beta 3 (h)-adrenergic receptor and serotonin receptors.
  • a composition which comprise antagonists against a receptor selected from the group of receptors comprising the alpha 2A (h)-, the apha 2B (h)- and the beta 2 (h)-adrenergic receptor are preferred.
  • ED erectile dysfunction
  • female sexual dysfunction are becoming increasingly more important as a result of the aging population. Because this subject is discussed widely in the media, men and women of all ages are seeking guidance in an effort to improve their relationships and experience satisfying sexual lives.
  • Sexual dysfunction is often associated with disorders such as diabetes, hypertension, coronary artery disease, neurologic disorders, and depression. In some patients, sexual dysfunction may be the presenting symptom of such disorders.
  • ED is often an adverse effect of many medications.
  • hormone deficiency is less often the cause of erectile dysfunction than diabetes or vascular disease are.
  • Vascular diseases account for nearly half of all cases of ED in men older than 50 years.
  • Vascular diseases include atherosclerosis, peripheral vascular disease, myocardial infarction, and arterial hypertension.
  • oral medications used to treat erectile dysfunctions include selective enzyme inhibitors such as sildenafil (sildenafil citrate, Viagra®), vardenafil HCl (Levitra®), tadalafil (Cialis®) and Yohimbine (Yohimbine®, Yocon®).
  • Alpha-adrenergic receptor blockade by phentolamine and similar compounds increases the efficacy of vasodilators in penile corpus cavernosum (Kim, 2000).
  • alpha-2 adreno receptor antagonists have been used for over a century in the treatment of erectile dysfunction using selective drugs such as yohimbine (Morales, 2000).
  • Thymoxamine moxisylyte
  • both antagonists of the alpha-1 and alpha-2 adreno receptors can be used in the treatment of erectile dysfunction (impotence).
  • a further embodiment of the invention is the use of a composition which comprise antagonists against a receptor selected from the group of receptors comprising alpha-adrenergic receptors for the manufacture of a product for treatment or prevention of erectile dysfunction in a mammal.
  • compositions which in addition to antagonists of the alpha-1 and alpha-2 adreno receptors further comprise beta-adreno receptor antagonists and even serotonin receptor antagonists and further compounds including the gamma butyric acid (GABA) will prove advantageous in the treatment of ED.
  • GABA gamma butyric acid
  • an embodiment of the present invention is the use of a composition which comprise antagonists against a receptor selected from the group of receptors comprising alpha-adrenergic, beta-adrenergic and serotonin receptors for the manufacture of a product for treatment or prevention of erectile dysfunction.
  • the product may further comprise agonists of GABA receptors such as GABA itself.
  • Benign prostatic hyperplasia is a common disease in aging males. It is characterized by a change in the size, composition, and function of the prostate gland and leads to obstruction of the bladder and urethra in middle-aged and elderly males.
  • the prostatic smooth muscle tone mediated primarily through alpha-1 adrenoceptors, appear to be a critical factor in the clinical manifestation of the BPH.
  • alpha-1 adrenoceptor antagonists have transformed BPH therapy from surgical to pharmacological intervention (Altwein, 1995; Barry and Roehrborn, 1997).
  • alpha-2 adrenoceptor antagonists appear to have beneficial influence on BPH.
  • an important embodiment of the present invention is the use of a composition obtained by fermentation of a food material which comprise antagonists against one or more receptors selected from the group of receptors comprising alpha-adrenergic receptors and beta-adrenergic receptors for the manufacture of a product for treatment or prevention of benign prostate hypertrophy (BPH) in a mammal.
  • BPH benign prostate hypertrophy
  • compositions obtained by fermentation of a food material which comprise antagonists against one or more receptors selected from the group of receptors comprising the alpha 1 A-, alpha 1 B-, alpha 2A (h)-, alpha 2B (h)-, alpha 2C (h)-, beta 1 (h)-, beta 2 (h)- and beta 3 (h)-adrenergic receptors and serotonin receptors.
  • a product which comprise antagonists against the alpha 2A (h)-, alpha 2B (h)- or beta 2 (h)-adrenergic receptor is preferred.
  • composition that is obtained by fermentation of a food material comprise more antagonists directed against different relevant receptors e.g. if the fermented food material comprises at least one component that is a ligand of an adrenergic and at least one component that is a ligand of a serotonin receptor, or if the fermented food material comprises at least one component that is a ligand of an adrenergic alpha receptor and at least one component that is a ligand of an adrenergic beta receptor. It is anticipated that the most relevant type of ligands are ligands that have the characteristics of being an antagonist of the receptors in case.
  • the unconcentrated fermentate contains antagonists in an amount that result in specific inhibition of specific receptors and which therefore is useful for prevention, relief and/or treatment of BPH and/or erectile dysfunction as well as for reducing heart rate in a mammal. Consequently, it is not necessary to further purify or up-concentrate the ligands from the fermented food material to obtain an effect according to the invention.
  • the fermented food material may be packed directly and provided to the market as a food product, preferably a functional food product, or a food product additive, e.g. in a freeze-dried form.
  • the fermented milk product of the present invention may be any known or future fermented milk product such as e.g. cheese, yoghurt and drinking yoghurt.
  • the product of the present invention may comprise living microorganisms eliciting a general health beneficial effect.
  • the product may also be described and marketed as a probiotic product.
  • Example 1 this is demonstrated.
  • the results of Example 1 show that fermented milk in itself without any further treatment has good heart rate reducing effect.
  • Further freeze-dried fermented milk could be suspended in neutral milk and thereby give a suitable food product with an effect according to the invention.
  • the freeze-dried fermented milk could therefore be seen as a suitable food additive product.
  • the product according to the present invention can be used for the prevention, relief and/or treatment of diseases and conditions where this specific receptor is involved.
  • diseases and conditions includes but are not limited to heart diseases, BPH and erectile dysfunctions.
  • the active component of the present invention is a ligand antagonist) of the several alpha-adrenoreceptors, beta-adrenoreceptors and even serotonin receptors opens up for combinational administration of the present product with drugs, compounds ligands etc. having a similar effect through another mode of action.
  • such further compounds include the Gamma butyric acid, referred to as GABA.
  • GABA Gamma butyric acid
  • the production of GABA results from the decarboxylation of glutamate (Glu) by the glutamate decarboxylase (GAD; EC 4.1.1.15), in which pyridoxal phosphate acts as the cofactor.
  • microorganisms especially lactic acid bacteria such as Lactobacillus sp., Lactococcus sp., Bifidobacterium sp. and Streptococcus sp, have glutamic acid decarboxylase activity and produce GABA from glutamic acid.
  • GABA has been of interest for many years, due to its health benefits.
  • This molecule constitutes one of the major inhibitory neurotransmitters of the central nervous system. It is found in brain and spinal cord of mammals and indeed very widely distributed in the neurons of the cortex and contributes to motor control, vision, and many other cortical functions. It facilitate blood flow in the brain to increase supply of oxygen so as to accentuate brain metabolism. Further GABA inhibit the secretion of vasopressin (antidiuretic hormone) to decrease the blood pressure by its vascular dilator action and decrease the blood pressure by acting on the vasomotor center of the spinal cord.
  • vasopressin antidiuretic hormone
  • GABA Acts Through the Receptors GABA-A and GABA-B Receptors.
  • any component that are an agonist of the GABA-A and/or GABA-B receptors e.g. GABA it self
  • any other potential component that are increasing the liberation of GABA in the human body may be included in the product e.g. the fermented milk product of the present invention.
  • the GABA content of the fermented food or feed product is ensured by including GABA producing microorganisms amongst the microorganisms used to perform the fermentation.
  • GABA-producing Streptococcus thermophilus are included.
  • the term “functional food” denotes herein a food product where the consumer in some way is informed that it has a useful function in relation to the diseases and/or conditions mentioned hereinbefore. When the term food is used it may also be feed. However, a food product is preferred.
  • an embodiment of the invention relates to a use as described herein where the composition is a food product comprising the active components with properties as described obtainable by a process comprising the following steps:
  • the term “packing” should be understood broadly. It denotes that once a food material is fermented and a fermented food material is obtained, the fermented food material should be packed in order to could be provided to the consumer. It may be packed in a bottle, a tetra-pack, etc. Preferably, on the package or in corresponding marketing material is indicated that the product has heart rate reducing properties. This applies for any aspects or embodiments of a product as described herein.
  • the lactic acid bacteria in the food product may be provided as cells of the bacteria.
  • Heat-treated fermented food material also elicited a heart rate reducing effect, consequently, the contemplated effects are to be expected from using cells of the lactic acid bacteria.
  • the fermented food product contains live bacteria cells that are beneficial to the health of a mammal host.
  • live bacteria cells are frequently referred to as probiotics.
  • probiotics constitute a class of microorganisms defined as live microbial organisms that beneficially affect animal or human hosts.
  • Lactic acid bacteria are in general recognised as being useful as probiotics or probiotically active organisms, especially lactic acid bacteria that are found among Lactobacillus, Streptococci and Bifidobacterium species (Fuller (1989)).
  • the heart rate reducing properties can be determined by administrating the product to spontaneous hypertensive rats (SHR) by gavage and determine the heart rate for 24 hours after gavage by telemetry in conscious SHR at different time points.
  • SHR spontaneous hypertensive rats
  • other animal models are useful for evaluating the heart rate efficacy of the fermented product.
  • One example is the model of normotensive Wistar rats described in example 4.
  • the product may be used in a treatment of a coronary artery disease (CAD) or a coronary heart disease (CHD) such as angina pectoris, hypertension, atherosclerosis, stroke, myocardial infarcation, cerebral infarction, and restenosis following angioplasty, arrhythmia, tachyarrythmia, congestive heart failure (CHF), aortic valve regurgitation, chronic renal failure, dyslipidemia, dyslipoproteinemia.
  • CAD coronary artery disease
  • CHD coronary heart disease
  • angina pectoris hypertension
  • atherosclerosis stroke
  • myocardial infarcation cerebral infarction
  • restenosis following angioplasty arrhythmia
  • tachyarrythmia congestive heart failure
  • CHF congestive heart failure
  • aortic valve regurgitation chronic renal failure
  • dyslipidemia dyslipoproteinemia
  • dyslipoproteinemia dyslipoproteinemia
  • Example 1 In addition to the conditions just mentioned the issue of fluctuations of the heart rate attracts interest.
  • Example 1 and 3 it is demonstrated that the fermented product effectively decreases heart rate but surprisingly also decreases fluctuations in the heart rate during the activity period of the experimental animals.
  • the damping of the fluctuations in the heart rate may be an important feature since changes in heart rate correlates with mortality in an experimental model (Zaza et al 2001).
  • the product may preferably be a food product or food additive, which people can consume in a daily or continuous manner.
  • the product has a heart rate reducing effect that is at least 10% over placebo where placebo is defined above as the corresponding unfermented food material.
  • the product has a heart rate reducing effect that is at least 15% over placebo, even more preferably the product has a heart rate reducing effect that is at least 20% over placebo and most preferably the product has a heart rate reducing effect that is at least 25% over placebo.
  • the use of the lactic acid bacteria, as described herein, provides directly after the fermentation a useful amount of the active components with very good heart rate reducing properties as well as contemplated effects on other conditions and diseases as previously mentioned.
  • the product is a medicament.
  • example 1 shows that the heart rate reducing effect is proportional to the concentration factor of the product.
  • an embodiment of the invention relates to a use as described herein where the fermented food material is further processed in a way that purify or up-concentrate the active components that is a ligand of the alpha-adrenoreceptors, beta-adrenoreceptors or serotonin receptors obtainable by a process comprising the following steps:
  • the process may comprise a further step (iv) where the up-concentrated active components of (ii) is added to the food product.
  • a preferred embodiment for up-concentration according to step (ii) above is where the fermented food material comprising the active components is centrifuged, and the resulting supernatant comprising the active components are recovered.
  • the food material is milk then such a product could be whey.
  • whey is a product with excellent heart rate reducing properties. Accordingly in a preferred embodiment the product is whey, however other fractions of the fermentated food or feed material may also be considered.
  • the centrifugation may preferably be performed, for example, at 2,000 to 20,000 rpm for 1 to 20 minutes.
  • the centrifugation may also be performed in a centrifugator.
  • the resulting supernatant may be subjected to further purifying treatment with a reverse-phase resin, for obtaining a sample in which the content of the active components is increased.
  • the purifying treatment with a reverse-phase resin may be performed by absorption and elution, by reverse-phase resin, and/or by reverse-phase chromatography, thereby increasing purity of the active components.
  • the fermented food material is further processed in a way wherein a nanofiltration is performed on the fermented food material. This may be done in order to remove lactic acid or monovalent ions from the fermented food material.
  • the food material is fermented by lactic acid bacteria under operating conditions, which may be varied depending on the types of the food material and/or the combination of the lactic acid bacteria.
  • the food material is not already an aqueous solution
  • food material is dissolved in a suitable aqueous solution, which is then admixed with lactic acid bacteria and cultivated by way of fermentation.
  • the culturing of the lactic acid bacteria may be performed by adding a pre-cultured lactic acid bacteria starter culture to the food material medium, which may have been previously heat-sterilized and cooled to the predetermined temperature for incubation.
  • the inoculation amount of the lactic acid bacteria starter may preferably be 10 5 to 10 7 cells of lactic acid bacteria/ml medium, however—depending on the specific starter culture—other amounts of starter cultures should be considered as well.
  • the temperature for incubation is usually 20 to 50° C. and preferably 30 to 45° C.
  • the incubation time is usually 3 to 48 hours and preferably 6 to 24 hours.
  • a preferred embodiment relates to a process, as described herein, wherein the fermenting of the food material is performed under conditions, which produce from 0.5 to 25 mg active components per 100 ml of the food material, more preferably which produce from 1 to 5 mg active components per 100 ml of the food material.
  • Mammal include animals such as domesticated animals (e.g. cats and dogs), pigs, cows, lambs. In a preferred embodiment the mammal is a human.
  • lactic acid bacterium designates a group of Gram positive, catalase negative, non-motile, microaerophilic or anaerobic bacteria that ferment sugar with the production of acids including lactic acid as the predominantly produced acid, acetic acid, formic acid and propionic acid.
  • lactic acid bacteria belonging to genus Lactobacillus such as Lactobacillus helveticus, Lactobacillus delbruekii subsp. bulgaricus , etc.
  • lactic acid bacteria belonging to genus Lactococcus such as Lactococcus lactis
  • lactic acid bacteria belonging to genus Streptococcus such as Streptococcus salivarius subsp.
  • thermophilus lactic acid bacteria belonging to genus Leuconostoc , such as Leuconostoc lactis , lactic acid bacteria belonging to genus Bifidobacterium , such as Bifidobacterium longum or Bifidobacterium breve , and lactic acid bacteria belonging to genus Pediococcus.
  • the lactic acid bacteria may be used as a mixture with other microorganisms, e.g. yeasts. Numerous different lactic acid bacteria are public available to the skilled person and it is contemplated that particular useful mixtures include a combination of Lactobacillus helveticus and Streptococcus thermophilus . Reference is e.g. made to Deutsche Sammlung von Mikroorganismen and Zellkulturen GmbH (DSMZ); and the Internet taxonomy browser of NCBI [at filing date available at worldwideweb.ncbi.nlm.nih.gov/.].
  • DSMZ Deutsche Sammlung von Mikroorganismen and Zellkulturen GmbH
  • a particular preferred embodiment relates to a use as described herein where the lactic acid bacterium is Lactobacillus helveticus with the registration number DSM 14998 is used.
  • the above mentioned strain DSM 14998 is used in combination with a Streptococcus thermophilus strain.
  • FIG. 1 Heart rate measurements in animals treated with concentration 3 (whey compositions containing solid whey components concentrated factor of 14.3 times) or placebo. Each data point is representing the average value from 8 animals. Note that the activity period of the animals is coincident with the period without light, i.e. the period indicated by the black bar.
  • FIG. 2 The reduction in heart rate in animals in the period 12-15 hours after the animals received whey compositions containing solid whey components concentrated 2, 6, 14.3 and 21 times relatively to the amount of solid components in whey obtained after fermentation of milk.
  • the animals were given the whey products by gavage, i.e. feeding by a stomach tube. (O) indicates placebo.
  • the heart rate was determined in animals as described in Example 1 and compared to the heat rate in untreated animals.
  • the milk (9.5% of protein content) was fermented with the strain of single culture for 16 hours with an inoculation level of 1% (v/v).
  • the fermented product was centrifuged, the pellet was discarded and the whey was filtered through a 0.45 mm filter and freeze-dried.
  • a second fermentation, fermented under the same conditions as the first one, was centrifuged and the whey fraction obtained.
  • the pellet was discarded and the whey was filtered through a 0.45 mm filter and frozen.
  • the whey was used to solubilize the freeze-dried whey powder to concentrate it with a factor 21 before feeding the rats.
  • the milk (9.5% of protein content) was fermented with the strain of single culture for 16 hours with an inoculation level of 1% (v/v). The total product was freeze-dried. A second fermentation, with the same conditions as the first one, was centrifuged. The pellet was discarded and the whey was filtered through a 0.45 mm filter and frozen. The whey was used to solubilize the freeze-dried fermented milk powder to concentrate it with a factor 5 before feeding the rats.
  • the milk (9.5% of protein content) was fermented with the strain of single culture for 16 hours with an inoculation level of 1% (v/v). The total product was freeze-dried. Milk (9.5% of protein content) was used to solubilize the freeze-dried powder to concentrate it with a factor 5 before feeding the rats.
  • the milk (9.5% of protein content) was fermented with the strain of single culture for 16 hours with an inoculation level of 1% (v/v).
  • the milk (9.5% of protein content) was fermented with the strain of single culture for 16 hours with an inoculation level of 1% (v/v).
  • Spontaneously Hypertensive Rats was obtained from IFFA CREDO (a Charles River company), Lyon, France.
  • Each treatment was administered between 9:15 h and 9:30 h by gavage and each animal received a total volume of 2.5 ml per animal.
  • Systolic blood pressure and heart rate were determined for 24 hours after gavage by telemetry (Data Sciences Int.) in conscious SHR at different time points.
  • Untreated Untreated 1 and untreated 2 are the controls of study 1 and study number 2, respectively. Untreated1 was the placebo for the sample 1 and untreated 2 was the placebo for all the other samples. We had two placebos because the studies were done independently in two different in vivo studies.
  • the whey part of the product that contains the peptides or other active components is determinant in the heart rate reducer effect.
  • Sample 3 is freeze-dried fermented milk suspended in neutral pH milk. It reduces the heart rate significantly. This demonstrates the wide application of a fermented product as described herein since it may be dissolved in different liquids to get a required final appropriate use. Characteristic such as different pH are not affecting the heart rate reducer activity of the product.
  • Sample 5 with heat treatment after fermentation reduces also the heart rate. Substantially all bacteria are killed in this sample. Accordingly, this demonstrates that there is no need to have live bacteria in the final product.
  • Sample 6 has not been fermented but it includes the live bacteria. It does not reduce the heart rate. It demonstrates that the fermentation step is required.
  • Example 1 To further substantiate the results presented in Example 1, a dose response experiment was performed by administering compositions containing variable amounts of freeze-dried whey obtained from fermented milk suspended in whey from fermented milk to Spontaneously Hypertensive Rats (SHR).
  • SHR Spontaneously Hypertensive Rats
  • milk was fermented with Lactobacillus helveticus strain CHCC5951 (DSM 14998) for 16 hours with an inoculation level of 1% (v/v).
  • the fermented milk was centrifuged, the pellet discarded and the whey freeze-dried.
  • a second fermentation with the same conditions as the first one was centrifuged.
  • the pellet was discarded and the whey was placed at 4° C.
  • the whey was used to solubilize the freeze-dried whey powder resulting in compositions containing solid whey components concentrated 2, 6 and 14.3 times relatively to the amount of solid components in whey obtained in the second fermentation.
  • the final step of the solubilization was done shortly before feeding the composition to the rats.
  • each testing-period was separated by a “wash out” period of three days in which animals did not received fermented whey product in order to eliminate the activity of the previous dose.
  • Placebo is non-fermented milk.
  • Concentration 1, 2 and 3 are whey compositions containing solid whey components concentrated 2, 6 and 14.3 times, respectively. Note that the activity period of the animals is coincident with the period without light, i.e. the time period from 9 to 21.
  • the variance of the heart rate values observed in the time period between 12 and 15 h was estimated.
  • the heart rate fluctuations is stabilized by the whey product fermented with Lactobacillus helveticus strain CHCC5951 (DSM 14998). This may be an important feature of the product since it has been observed that changes in heart rate correlated well with mortality in an experimental rabbit model (Zaza et al 2001) and since in particular in stressed situations significant heart rate fluctuations are frequently observed.
  • the purpose of this example was to compare a commercial lactic acid bacterium fermented milk product that is claimed to have blood pressure reducing properties with the product fermented with Lactobacillus helveticus strain CHCC5951 (DSM 14998).
  • the effect on blood pressure and heart rat of the two products was evaluated by administering the two compositions to Wistar rats and measuring the systolic blood pressure, the diastolic blood pressure and the heart rate on anaesthetized animals.
  • milk was fermented with Lactobacillus helveticus strain CHCC5951 (DSM 14998) for 16 hours with an inoculation level of 1% (v/v), and the resulting product was freeze-dried to obtain a freeze dried milk powder.
  • a second fermentation with the same conditions as the first one, was performed and centrifuged. The pellet was discarded and the whey was filtered through a 0.45 ⁇ m filter and frozen. Shortly before feeding it to the rats the freeze-dried milk powder was dissolved in the whey.
  • the amount of powder dissolved corresponded to the amount obtained from a volume of fermented milk that was 5 times the volume of the whey it was dissolved in (in casu 4.28 g powder in 30 ml of whey).
  • This composition we refer to as a ⁇ 5 concentration in this example.
  • the composition was administered to overnight fastened normotensive Wistar rats (300-320 grams) between 09:15 h and 09:30 h by gavage at a dose of 7.5 ml per kg of the ⁇ 5 composition.
  • the effect of the composition was evaluated between 14:30 h and 16:30 h, i.e. 5-7 hours after the oral administration by measuring the values of arterial blood pressure and heart rate on anaesthetized animals.
  • milk was fermented with Lactobacillus helveticus strain CHCC5951 (DSM 14998) for 16 hours with an inoculation level of 1% (v/v).
  • This fermentate was centrifuged, the pellet was discarded and the whey was separated in two parts. One part of the whey was freeze-dried. The other part of the whey was kept at +4° C. until used. This part is referred to as concentration 1 ⁇ .
  • the freeze-dried composition was kept at ⁇ 50° C. until reconstitution in an appropriate diluent.
  • a 200 ⁇ stock solution was prepared dissolving the freeze dried powder in a volumen of water resulting in a stock solution which was 200 ⁇ concentrated with respect to whey proteins relative to the non-freeze-dried whey composition.
  • More than one receptor is inhibited, underlining the complexity of the composition of the supernatant.
  • the various effects are most likely effected by different peptides with different target profiles.
  • the compounds present in the whey of the fermentate expresses the highest hibitory activity on the beta 2(h) (average 93%) and 5-HTns (average 93%) receptors, followed by alpha 2B(h)(average 68%)>alpha 2A(h) (average 64%)>alpha 2C(h) (average 50%) and alpha 1B(h) (average 47%).
  • the compounds inhibit the receptors beta 1(h) (average 39%) and alpha 1A(h) (average 34%).
  • the compounds are not active on the receptor beta3(h).
  • the applicant hereby requests that, until the application has been laid open to public inspection (by the Norwegian Patent Office), or has been finally decided upon by the Norwegian Patent Office without having been laid open inspection, the furnishing of a sample shall only be effected to an expert in the art.
  • the request to this effect shall be filed by the applicant with the Norwegian Patent Office not later than at the time when the application is made available to the public under Sections 22 and 33 (3) of the Norwegian Patents Act. If such a request has been filed by the applicant, any request made by a third party for the furnishing of a sample shall indicate the 'expert to be used. That expert may be any person entered on the list of recognized experts drawn up by the Norwegian Patent Office or any person approved by the applicant in the individual case.
  • the applicant hereby requests that, until the application has been laid open to public inspection (by the Danish Patent Office), or has been finally decided upon by the Danish Patent office without having been laid open to public inspection, the furnishing of a sample shall only be effected to an expert in the art.
  • the request to this effect shall be filed by the applicant with the Danish Patent Office not later that at the time when the application is made available to the public under Sections 22 and 33(3) of the Danish Patents Act. If such a request has been filed by the applicant, any request made by a third party for the furnishing of a sample shall indicate the expert to be used. That expert may be any person entered on a list of recognized experts drawn up by the Danish Patent Office or any person by the applicant in the individual case.
  • the applicant hereby requests that, until the application has been laid open to public inspection (by the Swedish Patent Office), or has been finally decided upon by the “Swedish Patent Office without having been laid open to public inspection, the furnishing of a sample shall only be effected to an expert in the art.
  • the request to this effect shall be filed by the applicant with the International Bureau before the expiration of 16 months from the priority date (preferably on the Form PCT/RO/134 reproduced in annex Z of Volume I of the PCT Applicant's Guide). If such a request has been filed by the applicant any request made by a third party for the furnishing of a sample shall indicate the expert to be used. That expert may be any person entered on a list of recognized experts drawn up by the Swedish Patent Office or any person approved by a applicant in the individual case.
  • the applicant hereby requests that until the date of a grant of a Netherlands patent or until the date on which the application is refused or withdrawn or lapsed, the microorganism shall be made available as provided in the 3 IF(1) of the Patent Rules only by the issue of a sample to an expert.
  • the request to this effect must be furnished by the applicant with the Netherlands Industrial Property Office before the date on which the application is made available to the public under Section 22C or Section 25 of the Patents Act of the Kingdom of the Netherlands, whichever of the two dates occurs earlier.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Zoology (AREA)
  • Biotechnology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Microbiology (AREA)
  • Wood Science & Technology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Mycology (AREA)
  • Genetics & Genomics (AREA)
  • Epidemiology (AREA)
  • Biochemistry (AREA)
  • Virology (AREA)
  • Cardiology (AREA)
  • Biomedical Technology (AREA)
  • General Engineering & Computer Science (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Botany (AREA)
  • Natural Medicines & Medicinal Plants (AREA)
  • Medical Informatics (AREA)
  • Cell Biology (AREA)
  • Developmental Biology & Embryology (AREA)
  • Immunology (AREA)
  • Alternative & Traditional Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Food Science & Technology (AREA)
  • Polymers & Plastics (AREA)
  • Gynecology & Obstetrics (AREA)
  • Endocrinology (AREA)
US11/660,659 2004-09-03 2005-09-05 Fermented milk or vegetable proteins comprising receptor ligand and uses thereof Expired - Fee Related US7883697B1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DK200401339 2004-09-03
DKPA200401339 2004-09-03
PCT/EP2005/054363 WO2006024673A1 (en) 2004-09-03 2005-09-05 Fermented milk or vegetable proteins comprising receptor ligand and uses thereof

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2005/054363 A-371-Of-International WO2006024673A1 (en) 2004-09-03 2005-09-05 Fermented milk or vegetable proteins comprising receptor ligand and uses thereof

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US13/021,392 Continuation US8367604B2 (en) 2004-09-03 2011-02-04 Fermented milk or vegetable proteins comprising receptor ligand and uses thereof

Publications (1)

Publication Number Publication Date
US7883697B1 true US7883697B1 (en) 2011-02-08

Family

ID=35344722

Family Applications (2)

Application Number Title Priority Date Filing Date
US11/660,659 Expired - Fee Related US7883697B1 (en) 2004-09-03 2005-09-05 Fermented milk or vegetable proteins comprising receptor ligand and uses thereof
US13/021,392 Expired - Fee Related US8367604B2 (en) 2004-09-03 2011-02-04 Fermented milk or vegetable proteins comprising receptor ligand and uses thereof

Family Applications After (1)

Application Number Title Priority Date Filing Date
US13/021,392 Expired - Fee Related US8367604B2 (en) 2004-09-03 2011-02-04 Fermented milk or vegetable proteins comprising receptor ligand and uses thereof

Country Status (12)

Country Link
US (2) US7883697B1 (zh)
EP (1) EP1796480B1 (zh)
JP (1) JP2008511593A (zh)
CN (1) CN101035433B (zh)
AT (1) ATE532416T1 (zh)
AU (1) AU2005279163B2 (zh)
BR (1) BRPI0514903A (zh)
CA (1) CA2577613C (zh)
DK (1) DK1796480T3 (zh)
NZ (1) NZ554278A (zh)
RU (1) RU2403051C2 (zh)
WO (1) WO2006024673A1 (zh)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110195891A1 (en) * 2004-09-03 2011-08-11 Chr-Hansen A/S Fermented milk or vegetable proteins comprising receptor ligand and uses thereof
ITPI20110033A1 (it) * 2011-04-01 2012-10-02 Funcional Food Res S R L Preparazione alimentare funzionale ad uso maschile.

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2009046456A (ja) * 2007-08-23 2009-03-05 Kikkoman Corp 生殖行動の誘発用組成物
ITTO20110631A1 (it) * 2010-07-15 2012-01-16 Oleg Iliich Epshtein Composizione farmaceutica di combinazione e metodi per trattare patologie del sistema genitourinario
FR2962656A1 (fr) 2010-07-15 2012-01-20 Oleg Iliich Epshtein Procede pour augmenter l'effet d'une forme activee-potentialisee d'un anticorps
FI126711B (fi) * 2011-10-12 2017-04-13 Gut Guide Oy Serotoniinivajeeseen liittyvän terveysriskin arvioiminen
WO2016182053A1 (ja) 2015-05-13 2016-11-17 アサヒカルピスウェルネス株式会社 運動時の心拍数上昇抑制方法及び心拍数上昇抑制組成物

Citations (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5436264A (en) * 1993-08-19 1995-07-25 Syntex (U.S.A.) Inc. N-aryloxyalkyl tryptamine α1 -adrenergic receptor antagonists
US5637617A (en) * 1994-04-01 1997-06-10 The Regents Of The University Of California Methods for use of GABAa receptor GABAergic compounds
EP0821968A2 (en) 1996-08-02 1998-02-04 The Calpis Food Industry Co., Ltd. Antihypertensive agent and method for preparing same
EP0966969A1 (en) 1996-08-07 1999-12-29 Calpis Co., Ltd. Anti-stress drugs and functional foods having anti-stress effects
EP1016709A1 (en) 1997-09-26 2000-07-05 Calpis Co., Ltd. Lactobacillus helveticus bacterium having high capability of producing tripeptide, fermented milk product, and process for preparing the same
WO2001032836A1 (en) 1999-11-01 2001-05-10 Valio Ltd Lactobacillus helvetius producing antihypertensive di- and tripeptides
US6303161B1 (en) * 1996-04-01 2001-10-16 Nichimo Co., Ltd. Product containing healthful component and process for preparing the same
WO2001085984A1 (en) 2000-05-08 2001-11-15 Davisco Foods International, Inc. Enzymatic treatment of whey proteins for the production of antihypertensive peptides, the resulting products and treatment of hypertension in mammals
US20030031625A1 (en) * 1999-08-11 2003-02-13 Lin Henry C. Methods of diagnosing irritable bowel syndrome and other disorders caused by small intestinal bacterial overgrowth
WO2003082019A2 (en) 2002-04-03 2003-10-09 Chr. Hansen A/S Peptides with anti-hypertensive properties
WO2004015125A1 (en) 2002-08-09 2004-02-19 Chr. Hansen A/S Process for preparing peptides with anti-hypertensive properties
US20040077624A1 (en) * 2002-05-23 2004-04-22 Pfizer Inc. Novel combination
US7048906B2 (en) * 1995-05-17 2006-05-23 Cedars-Sinai Medical Center Methods of diagnosing and treating small intestinal bacterial overgrowth (SIBO) and SIBO-related conditions

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020182274A1 (en) * 2001-03-21 2002-12-05 Kung-Ming Lu Methods for inhibiting cancer growth, reducing infection and promoting general health with a fermented soy extract
DK1796480T3 (da) * 2004-09-03 2012-02-13 Chr Hansen As Fermenterede mælkeproteiner, der omfatter receptor-ligand, og anvendelser deraf

Patent Citations (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5436264A (en) * 1993-08-19 1995-07-25 Syntex (U.S.A.) Inc. N-aryloxyalkyl tryptamine α1 -adrenergic receptor antagonists
US5637617A (en) * 1994-04-01 1997-06-10 The Regents Of The University Of California Methods for use of GABAa receptor GABAergic compounds
US7048906B2 (en) * 1995-05-17 2006-05-23 Cedars-Sinai Medical Center Methods of diagnosing and treating small intestinal bacterial overgrowth (SIBO) and SIBO-related conditions
US6303161B1 (en) * 1996-04-01 2001-10-16 Nichimo Co., Ltd. Product containing healthful component and process for preparing the same
EP0821968A2 (en) 1996-08-02 1998-02-04 The Calpis Food Industry Co., Ltd. Antihypertensive agent and method for preparing same
EP0966969A1 (en) 1996-08-07 1999-12-29 Calpis Co., Ltd. Anti-stress drugs and functional foods having anti-stress effects
US6596301B1 (en) * 1996-08-07 2003-07-22 Danone, Groupe Anti-stress drugs and functional foods having anti-stress effects
EP1016709A1 (en) 1997-09-26 2000-07-05 Calpis Co., Ltd. Lactobacillus helveticus bacterium having high capability of producing tripeptide, fermented milk product, and process for preparing the same
US20030031625A1 (en) * 1999-08-11 2003-02-13 Lin Henry C. Methods of diagnosing irritable bowel syndrome and other disorders caused by small intestinal bacterial overgrowth
WO2001032836A1 (en) 1999-11-01 2001-05-10 Valio Ltd Lactobacillus helvetius producing antihypertensive di- and tripeptides
WO2001085984A1 (en) 2000-05-08 2001-11-15 Davisco Foods International, Inc. Enzymatic treatment of whey proteins for the production of antihypertensive peptides, the resulting products and treatment of hypertension in mammals
WO2003082019A2 (en) 2002-04-03 2003-10-09 Chr. Hansen A/S Peptides with anti-hypertensive properties
US20040077624A1 (en) * 2002-05-23 2004-04-22 Pfizer Inc. Novel combination
WO2004015125A1 (en) 2002-08-09 2004-02-19 Chr. Hansen A/S Process for preparing peptides with anti-hypertensive properties

Non-Patent Citations (34)

* Cited by examiner, † Cited by third party
Title
A. Morales, "Yohimbine in erectile dysfunction: the facts", International Journal of Impotence Research (2000) 12, Suppl. 1, S70-A74.
A. Zaza et al., "Heart rate reduction: optimism with some caveats", http://ftp.escardio.org/newscast/stock2001/sipido.htm ; Mar. 8, 2005, pp. 1-2.
Anders Fuglsang et al., "Cardiovascular Effects of Fermented Milk Containing Angiotensin-Converting Enzyme Inhibitors Evaluated in Permanently Catheterized, Spontaneously Hypertensive Rats", Applied and Environmental Microbiology, Jul. 2002, pp. 3566-3569.
Andrew P. Feinberg et al., "A Technique for Radiolabeling DNA Restriction Endonuclease Fragments to High Specific Activity", Analytical Biochemistry, 132, 6-13 (1983).
Anton D. Michel et al., "Identification of a single beta1adrenoceptor corresponding to the alpha1A-subtype in rat submaxillary gland", Br. J. Pharmacol. (1989) 98, pp. 883-889.
Anton D. Michel et al., "Identification of a single β1adrenoceptor corresponding to the α1A-subtype in rat submaxillary gland", Br. J. Pharmacol. (1989) 98, pp. 883-889.
Barry Kenny et al., "alpha1-Adrenoceptor antagonists as treatments for benign prostatic hyperplasia", Exp. Opin. Invest. Drugs (1995) 4(10):915-923.
Barry Kenny et al., "α1-Adrenoceptor antagonists as treatments for benign prostatic hyperplasia", Exp. Opin. Invest. Drugs (1995) 4(10):915-923.
Carol Smith et al., "Beta-Blocker Selectivity at Cloned Human Beta1- and Beta 2- Adrenergic Receptors", Cardiovascular Drugs and Therapy 1999, 13:123-126.
Derwent Abstract 2004-180682,XP-002355394.
Dominique Langin et al., "[3H]RX821002: a new tool for the identificationof alpha2A-adrenoceptors", European Journal of Pharmacology, 167 (1989) 95-104.
Dominique Langin et al., "[3H]RX821002: a new tool for the identificationof α2A-adrenoceptors", European Journal of Pharmacology, 167 (1989) 95-104.
G.S.Brindley, "Pilot experiments on the actions of drugs injected into the human corpus cavernosum penis", Br. J. Pharmac. (1986), 87, 495-500.
Guthrie (Journal of Family Practice. 1994; 39 (2): 129-133). *
Jean-Christophe Devedjian et al., "Further characterization of human alpha2-adrenoceptor subtyptes: [3H]RX821002 binding and definition of additional selective drugs", European Journal of Pharmacology, 252 (1994) 43-49.
Jean-Christophe Devedjian et al., "Further characterization of human α2-adrenoceptor subtyptes: [3H]RX821002 binding and definition of additional selective drugs", European Journal of Pharmacology, 252 (1994) 43-49.
Jeffrey A. Pederson et al., "Genetic Characterization of a Cell Envelope-Associated Proteinase from Lactobacillus helveticus CNRZ32", Journal of Bacteriology, Aug. 1999, pp. 4592-4597.
Jens E Altwein et al., "Introduction: The Changing Therapy of Benign Prostatic Hyperplasia", Scand J Urol Nerphrol 29: 1-6, 1995.
M. Barry et al., "Management of Benign Prostatic Hyperplasia", Annu, Rev. Med. 1997, 48:177-189.
Malin C. Levin et al., "The Myocardium-protective Gly-49 Variant of the beta1-Adrenergic Receptor Exhibits Constitutive Activity and Increased Desensitization and Down-regulation", The Journal of Biological Chemistry, vol. 277, No. 34, Issues of Aug. 23, 2002. pp. 30429-30435.
Malin C. Levin et al., "The Myocardium-protective Gly-49 Variant of the β1-Adrenergic Receptor Exhibits Constitutive Activity and Increased Desensitization and Down-regulation", The Journal of Biological Chemistry, vol. 277, No. 34, Issues of Aug. 23, 2002. pp. 30429-30435.
NM Kim et al., "Alpha-adrenergic receptor blockade by phentolamine increases the efficacy of vasodilators in penile corpus cavernosum", International Journal of Impotence Research (2000) 12, Suppl. 1, S26-S36.
Pamela Greengrass et al., "Binding Characteristics of 3H-Prazosin to Rat Brain alpha-Adrenergic Receptors", European Journal of Pharmacology, 55 (1979) 323-326.
Pamela Greengrass et al., "Binding Characteristics of 3H-Prazosin to Rat Brain α-Adrenergic Receptors", European Journal of Pharmacology, 55 (1979) 323-326.
Patricia K. Curran et al., "Endogenous beta3- but Not beta1-Adrenergic Receptors Are Resistant to Agonist-Mediated Regulation in Human SK-N-MC Neurotumor Cells", Cell Signal, vol. 8 No. 5, pp. 355-364, 1996.
Patricia K. Curran et al., "Endogenous β3- but Not β1-Adrenergic Receptors Are Resistant to Agonist-Mediated Regulation in Human SK-N-MC Neurotumor Cells", Cell Signal, vol. 8 No. 5, pp. 355-364, 1996.
Pool (British Journal of Clinical Practice. 1994; 74: 13-17). *
R. Fuller, "Probiotics in man and animals", Journal of Applied Bacteriology, 1989, 66, 365-378.
Ronald F. Borne, "Serotonin: The Neurotransmitter for the '90s", Drug Topics, Oct. 10, 1994, pp. 1-16.
Staffan Uhlen et al., "Rat Spinal Cord alpha2-Adrenoceptors are of the alpha2A-Subtype: Comparison with alpha2A- and alpha2B-Adrenoceptors in Rat Spleen, Cerebral Cortex and Kidney Using 3H-RX821002 Ligand Binding", Pharmacology & Toxicology 1991, 69, 341-350.
Staffan Uhlen et al., "Rat Spinal Cord α2-Adrenoceptors are of the α2A-Subtype: Comparison with α2A- and α2B-Adrenoceptors in Rat Spleen, Cerebral Cortex and Kidney Using 3H-RX821002 Ligand Binding", Pharmacology & Toxicology 1991, 69, 341-350.
Stephen F. Altschul et al., "Gapped BLAST and PSI-BLAST: a new generation of protein database search programs", Nucleic Acids Research, 1997, vol. 25, No. 17 3389-3402.
Stephen J. Peroutka et al., "Multiple Serotonin Receptors: Differential Binding of [3H]5-Hydroxytryptamine, [3H]Lysergic Acid Diethylamide and [3H]Spiroperidol", Molecular Pharmacology, 16, 687-699, 1979.
Yoshiya Hata et al., "A placebo-controlled study of the effect of sour milk on blood pressure in hypertensive subjects", Am J Clin Nutr 1996, 64, 767-771.

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110195891A1 (en) * 2004-09-03 2011-08-11 Chr-Hansen A/S Fermented milk or vegetable proteins comprising receptor ligand and uses thereof
US8367604B2 (en) * 2004-09-03 2013-02-05 Chr-Hansen A/S Fermented milk or vegetable proteins comprising receptor ligand and uses thereof
ITPI20110033A1 (it) * 2011-04-01 2012-10-02 Funcional Food Res S R L Preparazione alimentare funzionale ad uso maschile.
WO2012131638A1 (en) * 2011-04-01 2012-10-04 Funcional Food Research S.R.L. Functional food for male use including muirapuamine and yohimbine

Also Published As

Publication number Publication date
RU2403051C2 (ru) 2010-11-10
CA2577613A1 (en) 2006-03-09
EP1796480A1 (en) 2007-06-20
WO2006024673A1 (en) 2006-03-09
JP2008511593A (ja) 2008-04-17
CA2577613C (en) 2015-12-15
ATE532416T1 (de) 2011-11-15
DK1796480T3 (da) 2012-02-13
AU2005279163A1 (en) 2006-03-09
US20110195891A1 (en) 2011-08-11
EP1796480B1 (en) 2011-11-09
BRPI0514903A (pt) 2008-06-24
AU2005279163B2 (en) 2012-02-02
CN101035433A (zh) 2007-09-12
CN101035433B (zh) 2011-09-07
US8367604B2 (en) 2013-02-05
NZ554278A (en) 2009-11-27
RU2007112116A (ru) 2008-10-10

Similar Documents

Publication Publication Date Title
US8367604B2 (en) Fermented milk or vegetable proteins comprising receptor ligand and uses thereof
US6596301B1 (en) Anti-stress drugs and functional foods having anti-stress effects
EP0778885B1 (fr) Preparation de produits fermentes par streptococcus thermophilus, enrichis en galacto-oligosaccharides et en beta-galactosidase
RU2744271C2 (ru) Пробиотическая композиция, содержащая штаммы Lactobacillus rhamnosus и Lactobacillus paracasei
US20100254956A1 (en) Probiotic bacteria and regulation of fat storage
NZ242195A (en) Enterococcus organisms and their use as probiotics in alleviating irritable bowel syndrome symptoms
JP4891069B2 (ja) 内因性メラトニン分泌リズムの位相調整又は振幅増強剤、及び概日リズム改善剤
FR2723960A1 (fr) Cultures de streptococcus thermophilus a activite beta-galactosidase elevee, leur procede d'obtention, et leurs utilisations
US10092605B2 (en) Food composition, containing Lactococcus strain as active ingredient, for alleviating hangover
KR20100126285A (ko) 항알레르기제
KR100942290B1 (ko) 김치유산균으로 발효한 콩 요구르트를 유효성분으로함유하는 우울증 예방 및 치료용 조성물
CN114365765A (zh) 具有降血压功能的牦牛酸乳及其制备方法
TW201625282A (zh) 新穎的醋酸桿菌菌株及葡糖酸醋酸桿菌菌株與其等用於抑制黃嘌呤氧化酶之代謝產物
Padghan et al. Studies on bio-functional activity of traditional Lassi
KR20090113477A (ko) 항고혈압활성 락토바실러스 플란타룸 및 이를 포함하는발효물
US7718171B2 (en) Reducing heart rate in mammals using milk derived fermentation products produced using Lactobacillus helveticus
JP2001226277A (ja) アルコール吸収代謝調整剤
Gurr The nutritional role of cultured dairy products
WO2004089097A1 (en) Composition with heart rate reducing properties
WO2004113509A1 (fr) Souche de lactobacillus casei lc2w et son utilisation contre l'hypertension
JP2012528826A (ja) ビタミンＫ強化ｔｈｙＡ（−）突然変異細菌
RU2064268C1 (ru) Напиток, способствующий адаптации организма к неблагоприятным условиям (варианты) и бактериальная закваска
KR19990007711A (ko) 항 콜레스테롤 유산균을 이용한 기능성 발효유 제조 방법
Gomaa et al. IMPACT OF Bifidobacterium befidium ON VITALITY AND QUALITIES OF BIO-YOGHURT MADE WITH DIFFERENT STRAINS OF LACTIC ACID BACTERIA
FR2739869A1 (fr) Ferment lactique, pour l'obtention de produits anti-diarrheiques.

Legal Events

Date Code Title Description
AS Assignment

Owner name: CHR-HANSEN A/S, DENMARK

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:FLAMBARD, BENEDICTE;REEL/FRAME:019164/0815

Effective date: 20070314

REMI Maintenance fee reminder mailed
LAPS Lapse for failure to pay maintenance fees
STCH Information on status: patent discontinuation

Free format text: PATENT EXPIRED DUE TO NONPAYMENT OF MAINTENANCE FEES UNDER 37 CFR 1.362

FP Lapsed due to failure to pay maintenance fee

Effective date: 20150208